Rheumatoid arthritis (RA) is estimated to occur in one to three percent of the general population and is one of the most common causes of disability. There is no known cure for rheumatoid arthritis and current disease modifying antirheumatic drugs (DMARDs) fail to address the underlying cause of the disease. Current rheumatoid arthritis treatment consists predominantly of symptomatic relief by administration of non-steroidal anti-inflammatory drugs (NSAIDs). NSAID treatment is mainly effective in the early stages of rheumatoid arthritis, and is unlikely to produce suppression of joint inflammation if the disease is present for more than one year.
Gold, methotrexate, immunosuppressants and corticosteroids have been tried with limited success. In advanced cases of rheumatoid arthritis, the traditional methods of treatment have generally been aimed at avoiding toxicity.
Disease modifying antirheumatic drugs also play a predominant role in the treatment of rheumatoid arthritis, but their toxicological profile limits their application and effectiveness in long-term therapy. For example, methotrexate (MTX) has demonstrated long-term efficacy, but its toxicological profile, e.g., gastrointestinal upset, mucosal ulcerations, renal impairment, pulmonary toxicity, is the most common reason cited among patients for treatment termination. The toxicity profile of MTX remains a major concern among physicians and prolonged treatment with MTX may require invasive biopsy procedures in a patient to monitor hepatic function. Another disease modifying antirheumatic drug, sulfasalazine, has been shown to be more effective than hydroxychloroquine in the treatment of rheumatoid arthritis, but it is not as well tolerated, with 20% of patients terminating treatment due to adverse gastrointestinal side effects. Azathioprine, penicillamine and gold compounds have also been shown to be efficacious in treating rheumatoid arthritis, but are not as well tolerated as MTX, sulfasalazine or hydroxychloroquine. Cylcosporine has shown applicability in treating rheumatoid arthritis, but its renal toxicity has limited its usage to salvage therapy or in combination therapy with other disease modifying antirheumatic drugs. Thus, treating rheumatoid arthritis with disease modifying antirheumatic drugs remains complicated by poor efficacy and the occurrence of adverse side effects. Lack of predictability of these adverse reactions has made regular monitoring of a patients physiological condition mandatory where long term therapy is anticipated. Such monitoring include, for example, measuring blood count, and/or performing liver, kidney, urine or ophthalmologic tests.
Historically, treatment of the inflammatory actions was available through the use of non-steroidal anti-inflammatory drugs (NSAIDs). This class of drugs possesses anti-inflammatory, analgesic and anti-pyretic activity, and are widely used to treat chronic inflammatory states such as arthritis. However, common NSAIDs that are active in reducing the PG-induced pain and swelling associated with the inflammation process are also active in affecting the other PG-roles which is not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved. Prostaglandins (PGs) play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of anti-inflammatory drug discovery. Along with this role, PGs play a cytoprotective role in the gastrointestinal tract and also on renal function. Previous NSAIDs have been found to prevent the production of PGs by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).
Cytokines are signaling peptide molecules that modulate a wide variety of cellular functions that includes inflammation. Cellular response occurs as a result of interaction between a particular cytokine and high-affinity cell-surface receptors specific for each cytokine. The receptor-binding event leads to the transduction of a signal across the cell membrane and the activation of intracellular biochemical pathways and gene translation or transcription events. Tumor Necrosis Factor-alpha (TNF-α) is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated tumor necrosis factor production has been implicated in mediating a number of diseases. Recent studies indicate that tumor necrosis factor has a causative role in the pathogenesis of rheumatoid arthritis. Additional studies demonstrate that inhibition of tumor necrosis factor has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
Interleukin-8 (IL-8) is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.
Interleukin-1 (IL-1) is produced by activated monocytes and macrophages and is also involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
Rau et al., J. Rheumatol. 25 (1998), 1485-1492, describe a combination of methotrexate (MTX) and parenteral gold or MTX and other disease modifying antirheumatic drugs (DMARD) in the treatment of rheumatoid arthritis. Conagham and Brooks, Curr. Opin. Rheumatol. 8 (1996), 176-182, describe methotrexate in combination therapy with intramuscular gold and other DMARDs for the treatment of arthritis. Fürst, J. Rheumtol., Suppl. 44 (1996) Rheumatoid Arthritis: The Status and Future of Combination Therapy, 86-90, reviews 16 references and describes an approach to rheumatoid arthritis disease modifying drug combination therapy. Li, Curr. Opin, Rheumatol. 10 (1998), 159-168, describes certain disease modifying anti-rheumatic drugs in combination therapy in patients suffering from rheumatoid arthritis. Conagham et al., Curr. Opin. Rheumatol. 9 (1997), 183-190, describes MTX, sulfasalazine, and hydroxychloroquine in combination therapy for the treatment of rheumatoid arthritis. O'Dell et al., J. Rheumatol. Suppl. 44 (1996) Rheumatoid Arthritis: The Status and Future of Combination Therapy, 72-74, describe the single agent therapy of MTX, sulfasalazine or hydroxychloroquine and the combination of MIX, sulfasalazine and hydroxychloroquine, and MTX in combination with either sulfasalazine or hydroxychloroquine. Dijkmans et al., J. Rheumatol. Suppl. 44 (1996), 61-63, describes a 2 phase study using a combination of cyclosporin A (CsA) (an inhibitor of interleukin 2 (IL-2) and other cytokine production) with chloroquine for the treatment of rheumatoid arthritis.
The state of the art as regards several approaches for the treatment of inflammatory diseases is summarized in WO01/00229, which in addition describes combinations of a tumor necrosis factor antagonizing agent and a cyclooxygenase-2 inhibiting agent for treating inflammatory disease in a mammal.
Despite these and other advances, a great need remains for better therapies for inflammatory disease, in particular for rheumatoid arthritis. The solution to said technical problem is achieved by providing the embodiments characterized in the claims, and described further below.